Buprenorphine (Formula 1) is a semisynthetic opioid derivative of thebaine. It is a mixed agonist—antagonist opioid receptor modulator that is used to treat opioid addiction in higher dosages, to control moderate acute pain in non-opioid-tolerant individuals in lower dosages and to control moderate chronic pain in even smaller doses. Buprenorphine is absorbed in the gastrointestinal tract and acts systemically.

Naloxone (Formula 2) is a pure opioid antagonist. Naloxone is a medication used to reverse opioid-induced depression of the central nervous system, respiratory system, and hypotension. Naloxone may be combined with opioids that are taken by mouth to decrease the risk of their misuse. Naloxone is absorbed in the gastrointestinal tract and may act systemically, leading to opioid withdrawal symptoms.

Naltrexone (Formula 3) is an opioid antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride. It is also absorbed in the gastrointestinal tract and acts systemically. Like naloxone, naltrexone may induce opioid withdrawal symptoms.

Des-venlafaxine (Formula 4) also known as O-desmethylvenlafaxine, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. It has been considered for use in the treatment of chronic idiopathic constipation and gastroparesis, but because it acts systemically and its CNS effects can include sexual dysfunction its use for those purposes in persons not suffering from depression is contra-indicated.

Acetaminophen (Formula 5), chemically named N-acetyl-p-aminophenol, is one of the most widely used medications in the United States. It is over-the-counter analgesic and antipyretic, commonly sold under the trade name Tylenol®. Acetaminophen is classified as a mild analgesic. It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies. In combination with opioid analgesics, acetaminophen can also be used in the management of more severe pain such as post-surgical pain and providing palliative care in advanced cancer patients. The quinone metabolite of acetaminophen is hepatotoxic. While usual dosing of acetaminophen is considered harmless, both acute and chronic overdoses can be fatal.

Albuterol (Formula 6) is a short-acting β2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease. It relaxes muscles in the airways and increases air flow to the lungs. Albuterol is also used to prevent exercise-induced bronchospasm. It is usually given by inhalation to sidestep high first pass metabolism in the liver. Its highly variable bioavailability has been attributed to its phenolic hydroxyl group.

What these agents have in common is a single phenolic hydroxyl group. Such groups confer photo instability and undergo rapid presystemic or first pass metabolism in the gastrointestinal tract, variously forming sulfate esters or glucourinide esters. Buprenorphine and desvenlafaxine are also subjected to enzymatic degradation (CYP3A4 and CYP2A6). To sidestep consequent diminution in bioavailability, agents like buprenorphine and naloxone are most commonly administered by injection or sublingually.
Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D)
IBS-D is a highly prevalent gastrointestinal disorder that is often accompanied, in addition to diarrhea, by both visceral hyperalgesia (enhanced pain from colorectal stimuli), discomfort, bloating, and gas.
Eluxadoline® (Forest Laboratories, Inc.) is a μ opioid receptor agonist and δ opioid receptor antagonist that has met primary endpoints of improvement in stool consistency and reduction of abdominal pain in Phase III testing, albeit without a demonstrable effect on reducing colonic hypersensitivity that results in hyperalgesia. Moreover, several cases of pancreatitis, a potentially life threatening disease, were reported in Phase II trials. Cases of pancreatitis were reported even after patients with a known history of biliary disease were excluded from clinical study enrollment. In general, μ agonists have a constricting effect on the Sphincter of Oddi, a muscular valve that regulates the flow of bile and pancreatic juice from the bile duct into the duodenum. It is very important that a drug with μ-receptor agonist activity and that is prescribed for long-term use, not lead to constriction of the Sphincter of Oddi.
There has accordingly been a long-standing need for a chronic treatment of IBS-D that decreases intestinal motility, thereby decreasing the incidence of diarrhea, is an analgesic, is not associated with pancreatitis, and more than merely treating symptoms, addresses underlying hypersensitivity and resulting hyperalgesia associated with IBS-D.